JP2005505500A - Use of proteins and essential amino acids to treat amenorrhea and related diseases - Google Patents
Use of proteins and essential amino acids to treat amenorrhea and related diseases Download PDFInfo
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- JP2005505500A JP2005505500A JP2002584908A JP2002584908A JP2005505500A JP 2005505500 A JP2005505500 A JP 2005505500A JP 2002584908 A JP2002584908 A JP 2002584908A JP 2002584908 A JP2002584908 A JP 2002584908A JP 2005505500 A JP2005505500 A JP 2005505500A
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Abstract
体重減少を招く栄養不良は女性のエストロゲン分泌を妨げ、よって骨密度及び月経周期に対して有害作用が生ずる。本発明は、タンパク質摂取量を全タンパク質または必須アミノ酸のブレンドとして増加させることにより栄養不良の代謝作用を逆転させ得るという知見に基づいている。前記タンパク質は食事サプリメントの形態で、食品として、または完全食の成分として投与され得る。Malnutrition leading to weight loss interferes with women's estrogen secretion, thus adversely affecting bone density and menstrual cycle. The present invention is based on the finding that increasing the protein intake as a whole protein or a blend of essential amino acids can reverse the metabolic effects of malnutrition. The protein can be administered in the form of a dietary supplement, as a food, or as a component of a complete diet.
Description
【技術分野】
【０００１】
本発明は、無月経及び関連する医学的疾患の治療及び予防方法、特に前記症状を逆転させる食事手段に関する。
【背景技術】
【０００２】
最近、神経性拒食症や過食症のような摂食障害を特に若い女性の中で診断する際に不安が生じている。しばしば激しい運動と組み合わされるダイエットにより、エネルギー摂取量が非常に不足するようになり得る。時にエネルギー要件を満足するのに十分なカロリーを消費できない人々は激しい肉体トレーニングを受けている運動選手達である。ひどい栄養不良の場合には、身体は生存のために非必須代謝プロセスを切り詰めることにより適応している。
【０００３】
少女及び女性の中で、体重がひどく減少したり体重増加がないために低体重を有する最も顕著な症状の１つは無月経（すなわち、排卵が止まったために月経周期がない）である。厳しい食事制限の状態で見られるエネルギー摂取量の低下はこうした状況での無月経の主因であると考えられる。
【０００４】
長い間の無月経は健康に非常に重大な結果を伴う。例えば、無月経と受精能力の間には強い相関関係がある。また、血中の循環エストロゲンのレベルが低いために成長中の骨量獲得が低下し、成人期に骨損失が引き起こされる。低いボディ・マス・インデックス（ＢＭＩ）は骨粗しょう症の危険因子と見做されている。神経性拒食症の女性では、骨形成マーカーであるオステオカルシンの血清レベルは年令に適合する健康人のレベルと比較して有意に低下している。無月経の女性が特に晩年に骨粗しょう症や骨折にかかりやすいことは常識である。
【０００５】
不妊や脆い骨に起因する個人的有害ストレスを避け、前記疾患の治療に関わる医療関係者への負担を制限するために、無月経女性の月経周期を直ぐに正常に戻すことができる治療が緊急に求められている。
【０００６】
栄養不良の無月経女性が自発的にバランスのよい摂食パターンと十分なカロリー量の食事を再開することが理想的である。しかしながら、神経性拒食症及び他の摂食不足／過剰運動障害は一生ヒトを苦しめることがある慢性的な症状であるので、このことは通常非現実的である。患者は食事のカロリー量を増やせという一般的な医学的アドバイスに服従しないことが多い。同様に、運動選手はしばしば身体をピークの肉体コンディションに保ち、カロリー消費をコントロールすることにより体脂肪量を最小限とすることに関心を持っている。
【０００７】
現在の臨床療法では、飢餓により止まったり不規則な月経周期を回復するためにエストロゲン治療を通常採用している。しかしながら、この効果は非常に疑わしく、副作用も伴っており、エストロゲンが癌発達を促進させる可能性があることも注目されている。カルシウム及びビタミンＤサプリメントも無月経の栄養不良女性における骨サポートのためにしばしば処方されている。しかしながら、その治療は性ホルモン欠乏及び低タンパク質摂取という負の効果を完全にうち消すことができない。
【０００８】
本出願人は、食事療法により正常なホルモン周期及び月経を迅速に再開させることができ、体重減少に起因する無月経を経験している女性の骨ミネラル密度（ＢＭＤ）及び体重を増加させ得ることを示す前例のない実験結果を得た。上記結果を得るためには食事タンパク質摂取を増加させることが重要である。予期せぬことに、必須アミノ酸のブレンドは完全食事タンパク質と丁度同じように有効である。予期に反して、所望効果が全エネルギー消費の増加に関係なく、場合により増加させずに得られる。従って、この治療方法は全カロリー摂取量を増加させたくない無月経の女性、特に脂肪または炭水化物消費が嫌な無月経の女性に理想的に適している。
【０００９】
体重減少に起因する無月経を治療するためのタンパク質サプリメントまたは食事は副作用の危険を伴わずに長期間自己投与され得、性ホルモンのバランスが悪いために生ずる身体への長期間ダメージを予防するために非常に有効である。
【発明の開示】
【００１０】
本発明の第１態様によれば、栄養不良を患っている閉経前女性のエストロゲンレベルを生理学的に正常なレベルに戻すための薬剤または栄養剤の製造における２つ以上の遊離形態または塩形態の必須アミノ酸の使用を提供する。
【００１１】
本発明の別の態様によれば、無月経、過少月経または迷走性月経、特に栄養不良に起因するこれらの病気を予防または治療するための薬剤または栄養剤の製造における２つ以上の遊離形態または塩形態の必須アミノ酸の使用を提供する。
【００１２】
本発明の更なる態様によれば、無月経、過少月経または迷走性月経を患っている閉経前女性における骨減少症または骨粗しょう症を予防または治療するための薬剤または栄養剤の製造における２つ以上の遊離形態または塩形態の必須アミノ酸の使用を提供する。
【００１３】
本発明の更なる態様によれば、栄養不良に起因する無月経、過少月経または迷走性月経を患っている閉経前女性の体重減少及び／または筋肉量低下を予防または逆転するための薬剤または栄養剤の製造における２つ以上の遊離形態または塩形態の必須アミノ酸の使用を提供する。
【００１４】
本発明の更なる態様によれば、栄養不良を患っている閉経前女性の無月経、過少月経または迷走性月経を予防または治療するための、少なくとも２０ｅｎ％のタンパク質を含み、炭酸または無炭酸ソフトドリンク、ジュース、スポーツドリンク、ミルクドリンク、ミルクシェーク、ヨーグルトドリンク、スムージー、大豆ベースドリンク、スープ、棒状シリアル、棒状乳製品、スナックフード、朝食用シリアル、キャンディー、タブ、クッキー、クラッカー、チョコレート、チューイングガムまたはデザートの形態である薬剤または栄養剤におけるタンパク質の使用を提供する。
【００１５】
本発明の更なる態様によれば、無月経、過少月経または迷走性月経を患っている月系前女性において栄養不良に起因する骨減少症または骨粗しょう症を予防または治療するための少なくとも２０ｅｎ％のタンパク質を含む完全処方食または経腸栄養補給液の製造におけるタンパク質の使用を提供する。
【００１６】
本発明の更なる態様によれば、栄養不良を患っている閉経前女性の無月経、過少月経または迷走性月経を予防または治療するための少なくとも２０ｅｎ％のタンパク質を含む完全処方食または経腸栄養補給液の製造におけるタンパク質の使用を提供する。
【００１７】
本発明の更なる態様によれば、遊離形態または塩形態のロイシン、リジン、イソロイシン、フェニルアラニン、バリン、アルギニン、トレオニン、ヒスチジン及びトリプトファンからなるアミノ酸のブレンドを含む骨減少症、骨粗しょう症、無月経、過少月経または迷走性月経を予防または治療するための医薬または栄養組成物を提供する。
【００１８】
（発明の詳細説明）
本発明の方法は、通常栄養不足または栄養不良女性に適用され得る。本明細書中、用語「女性」は閉経前女性、並びに思春期に近づいている（思春期前）または思春期後の少女を指す。多くの女性は一生のあるときに自らにダイエットを課しており、血中エストロゲンレベルが低下したり骨のカルシウム沈着に影響を与える危険性を潜在的に有しているので、栄養不良及び栄養不足の女性の数は多い。低開発国の多数の女性も食物不足のために慢性的に栄養不足または飢餓の状態にあり、本発明の方法は女性の健康を取り戻すのに簡単であるが実際的な方法である。
【００１９】
栄養不足の若い（１５〜３５才）女性は本発明の治療方法の恩恵を最も受けやすい。なぜならば、この年頃は骨量がピークに達する時期であり、この傷つきやすい年頃に骨密度が高まらないと晩年女性が骨粗しょう症にかかる可能性が高いからである。年令及び性に適合した正常値以下の２標準偏差を越える骨密度を有する患者は骨損失を止め、好ましくは逆転させるために本明細書に記載されているような治療を直ちに受ける必要がある。１５〜３５才の女性は妊娠を最も望んでおり、よって栄養不良に起因する受精能力に対する負の効果を最小限にすることが望まれている。
【００２０】
上記した理由で、神経性拒食症や神経性過食症のような摂食障害を患っている無月経または過少月経患者は生殖系及び骨格に対する不可逆的ダメージを避けることに至急注意しなければならず、本明細書に記載されている治療方法の主たる対象である。前記治療が意図される他の対象には、非常に活発な女性、特にダンサー及び持久力を要する運動選手が含まれる。低体重であるが体重減少の目的でエネルギー摂取量を制限しているか制限しようとしている女性、及び菜食主義者や厳格菜食主義者、または正常月経周期を維持するには食事のバランスが適切でない女性も本発明の治療方法の好適な対象である。
【００２１】
栄養不良は、カロリー摂取量が身体の異化作用のバランスを取るのに必要な量よりも繰り返し不足しているかまたは食事の組成のバランスが悪いために起こり得る慢性的な栄養不足または飢餓の状態であり得る。食事の栄養学者、栄養士または他の専門家による分析から、個人が栄養不良であるかまたは栄養不良になる危険な状態にあるかが示される。本発明では、栄養不良状態は低体重及び／または低体脂肪量及び／または低血清レプチン濃度で分かると見做される。低体重は２０未満、特に１８未満のＢＭＩとして定義される。約１５〜１７％以下の体脂肪量は低いと見做される。体脂肪量とレプチンレベルには相関関係があるので、このホルモンの血清濃度が５ｎｇ／ｍｌ未満、特に１．８５ｎｇ／ｍｌ未満のときには本発明の治療方法を月経異常を予防または改善するために始めるべきである。
【００２２】
本発明において、無月経は妊娠していない閉経前女性において月経がない、特に６ヶ月以上ない状態と定義される。原発性無月経では初潮がない、すなわち月経が今までに起こっていない。続発性（視床下部性）無月経では、月経が少なくとも１周期後止まっている。過少月経は、２年以上にわたり月経出血が１年あたり３回以下の場合と定義される。本発明の治療方法は、低体重／体脂肪量、または急速な体重低下を伴っている（原発性または続発性）無月経、過少月経、或いは迷走性または不規則性月経に対して特に適用され得る。本発明の治療方法の１つの目的は、月経周期を女性にとって正常であると見做される頻度で規則的な周期に戻すことである。本発明を定義するために、エストロゲンの正常な生理学的レベルは≧３０ｐｇ／ｍｌの血清エストラジオールであり、３０ｐｇ／ｍｌ以上でなければ排卵は再開しないであろう。血清エストラジオールを好ましくは１００〜７００ｐｇ／ｍｌ、最も好ましくは２００〜４００ｐｇ／ｍｌの範囲の値に回復させる。月経が部分的にしか回復しなかったり不規則な場合にも、骨ミネラル密度（ＢＭＤ）の改善と共に循環エストロゲンレベルの部分的回復を示し得る。
【００２３】
本発明の改良された無月経の治療方法の最大の作用効果の１つは、従来方法に反して、症状を逆転させるために食事の全エネルギー量を増加させる必要が全くないことである。実際、等カロリー量を維持しながら食事の他の主要成分（脂肪及び炭水化物）に対するタンパク質の割合を単に増加させることは正常な月経周期を回復させる驚くほど有効な方法である。その結果、神経性拒食症や他の摂食障害を患っている女性のようなカロリー摂取量を増加させたくない女性は強制栄養を含む従来方法よりもこの新しい改良治療法を受け入れやすい。本発明の目的では、食事の全カロリーの±１０％以下、特に±５％以下の変更が実質的な変化がないと見做される。すなわち、食事は等カロリーである。
【００２４】
下記実施例は、タンパク質が不足しているような栄養不足に応答して見られる低ＢＭＩが食事中のタンパク質（カゼインまたは必須アミノ酸（ＥＡＡ）ブレンド）の割合を増加させると有意に改善されることを示す。この結果は医学的にすばらしい。なぜならば、閉経前女性において栄養不良に関連する骨格衰弱をエストロゲンまたは他の薬物による治療を必要とせずに食事の組成を変更することにより回復させ得ることが初めて立証されたからである。多分、タンパク質追加の主たる効果はエストロゲン分泌及び月経周期を回復させ、最終的に骨構造に影響を与えることである。従って、本発明の方法は栄養不良に伴って骨減少症及び骨粗しょう症を患っているかまたは将来患う危険がある閉経前女性に対して有効である。
【００２５】
本発明の薬剤または栄養剤は専らタンパク質から構成され得るか、またはタンパク質に加えて他の栄養成分を配合してもよい。本明細書中、「タンパク質」または「タンパク質様物質」は消化性タンパク質、ペプチド、単一アミノ酸、アミノ酸混合物及びその組合せを指す。好ましいタンパク質は乳タンパク質、カゼイン、ホエー及び加水分解物またはそのペプチド、卵タンパク質、植物タンパク質（例えば、大豆タンパク質、エンドウ豆タンパク質、米タンパク質または小麦タンパク質）、遊離アミノ酸及びその混合物である。アミノ酸を指すとき、この用語は水和物または無水物形態の遊離アミノ酸のＬ形態またはその他の異性体、並びに前記アミノ酸の塩を包含すると理解される。
【００２６】
特に、本発明の組成物のタンパク質成分に１つ以上、好ましくは少なくとも２つの必須アミノ酸を配合することが好ましい。必須アミノ酸（ＥＡＡ）はヒスチジン、イソロイシン、ロイシン、リジン、メチオニン、フェニルアラニン、トレオニン、トリプトファン及びバリンである。本発明の１実施態様では、本発明の組成物のタンパク質成分は少なくとも３０重量％（好ましくは、少なくとも４５重量％）の分枝鎖アミノ酸（バリン、イソロイシン、ロイシン）を含む。「ＥＡＡブレンド」または「ＥＡＡ組成物」は、少なくとも１つのＥＡＡを含む組成物を指すと理解されたい。選択される特定アミノ酸ブレンドは治療対象の患者により異なり得る。例えば、菜食主義者または厳格菜食主義者は植物材料中に存在しないアミノ酸を含む製品の恩恵を多く受け得る。本発明の方法で治療しようとする患者が食欲不振であるかまたは食べたくない人の場合には、セロトニンレベルと食欲不振には関係があると仮定されているので組成物中に遊離アミノ酸形態のトリプトファンを配合しないことが推奨され得る。場合により、ヒトに対してメチオニンを除いたすべての必須アミノ酸の混合物を使用することができる。
【００２７】
本発明の好ましい実施態様では、本発明の特別食中に配合されるタンパク質はロイシン、リジン、イソロイシン、フェニルアラニン、バリン、アルギニン、トレオニン、ヒスチジン及びトリプトファンから選択される１つ以上のアミノ酸のブレンドからなり、場合により追加のタンパク質を添加してもよい。例えば、アミノ酸は重量基準で以下の相対比：
ロイシン １．０−１．５
リジン ０．７５−１．０
イソロイシン ０．４−０．７５
フェニルアラニン ０．３５−０．６
バリン ０．２５−０．６
アルギニン ０．２５−０．６
トレオニン ０．２５−０．５
ヒスチジン ０．２５−０．５
トリプトファン ０−０．２５
で存在し得る。
【００２８】
特に好ましい製剤は、アミノ酸の全重量に対する重量基準で、２４〜２８％のロイシン、１４〜１８％のリジン、１０〜１４％のイソロイシン、１０〜１４％のフェニルアラニン、８〜１２％のバリン、６〜８％のアルギニン、６〜８％のトレオニン、６〜８％のヒスチジン及び２〜３％のトリプトファンのアミノ酸組成を有する。
【００２９】
場合により、本発明の組成物のタンパク質成分は専らまたは本質的に本明細書に記載の遊離アミノ酸のブレンドから構成される。より一般的には、タンパク質成分は全タンパク質及び遊離アミノ酸を好ましくは１：５〜５：１の重量比で含む。必須アミノ酸のブレンドと共にホエータンパク質を含む製剤を使用してもよい。本発明の好ましい実施態様では、タンパク質成分はホエータンパク質及びアミノ酸ブレンドを約２：１〜４：１、好ましくは約３：１の重量比で含む。本発明の栄養剤または薬剤の総タンパク質含量は該栄養剤または薬剤の総カロリーに基づいて好ましくは少なくとも２０ｅｎ％（エネルギー％）、または少なくとも２５ｅｎ％、例えば２５〜１００ｅｎ％、好ましくは３０〜９０ｅｎ％、最も好ましくは４０〜８０ｅｎ％である。
【００３０】
場合により、タンパク質を経口または給管栄養に適している栄養学的にバランスのとれた完全食の形態で提供する。すべての栄養要件を満たす完全処方食または完全食はタンパク質に加えて脂肪及び炭水化物を含み、更に（可溶性及び／または不溶性）繊維、ミネラル及びビタミンを含む。処方食または他の形態のバランスのとれた栄養食の場合、タンパク質：脂肪：炭水化物の相対比率（ｅｎ％）は場合により２５〜３５：８〜３０：４０〜６５である。タンパク質を低カロリー代用食または他の栄養食の形態で提供することが望ましいことがある。この場合、低カロリー代用食または他の栄養食は好ましくは低脂肪（すなわち、＜１０ｅｎ％）または実質的に無脂肪（すなわち、２．５ｅｎ％未満、例えば約２ｅｎ％）である。好適には、低カロリー代用食の一人分は１０００ｋｃａｌ未満、好ましくは２００〜５００ｋｃａｌのカロリー値を有する。
【００３１】
或いは、タンパク質は所望量のタンパク質またはタンパク質からのカロリー分が達成されるような量食事に含まれる食事サプリメントとして提供される。食事中のタンパク質の所望カロリー分は全部で少なくとも２５ｅｎ％、より好ましくは少なくとも３０ｅｎ％である。
【００３２】
本発明の食事レジメによれば、女性が全部で少なくとも１０ｇ／日、好ましくは１５〜２００ｇ／日、最も好ましくは２０〜１００ｇ／日のタンパク質を消費することを意図している。
【００３３】
本発明の薬剤または栄養剤は医学的専門家の監視下で投与されるかまたは自己投与され得る。
【００３４】
便宜上、タンパク質／アミノ酸含有製剤は完全食として、溶解用粉末（例えば、ホットチョコレートまたは健康ドリンク）として、溶液として、ジュース，ミルクシェーク，ヨーグルトドリンク，スムージーまたは大豆ベースのドリンクを含めたソフトドリンクのような場合により低カロリーの用時調製ドリンクとして、棒状の経口栄養形態で提供され得、或いはベークド食品，シリアルバー，棒状乳製品，スナックフード，スープ，朝食用シリアル，ム−スリ，キャンディー，タブ，クッキー，ビスケット，クラッカー（例えば、ライスクラッカー），チョコレート及び乳製品のような任意の種類の食物中に分散され得る。肉体的に活動的な女性、特にスポーツウーマン、ダンサーや神経性無食欲症患者のような過剰運動の女性に対しては、スポーツドリンクがタンパク質サプリメントを与えるのに非常に便利な方法である。好ましくは、スポーツドリンクは等張性であり、電解質及び糖または人工甘味料のソースを含む。場合により製剤は給管栄養補給液の形態でまたは静注投与され得る。
【００３５】
本発明の好ましい実施態様では、本発明のタンパク質成分はカルシウム、マグネシウム、鉄、亜鉛、リン、ビタミンＤ及びビタミンＫの１つ以上をも含む医薬または栄養組成物で投与される。好適な１日量は０．１ｍｇ〜３．６ｇ、好ましくは３２０〜５３０ｍｇ、特に好ましくは約５００ｍｇのカルシウムである。通常、本発明の栄養剤または薬剤中のビタミン及びミネラルの１日用量は健康専門家が推奨する用量の２５〜１００重量％、最も好ましくは３５〜５０重量％である。食物繊維も本発明の組成物の１成分であり得る。例えば、繊維成分は組成物の全重量に基づいて０〜１５重量％、好ましくは２〜１０重量％、最も好ましくは３〜５重量％存在し得る。サプリメントの追加成分には、健康に良いとして公知の生物活性化合物または抽出物、特に骨の構築、ホルモンインバランスの調節及び／または肉体的機能の改善のために生物活性化合物または抽出物が含まれ得る。
【００３６】
保存剤、キレート剤、飽和剤、天然または人工甘味料、フレーバー、着色剤、味マスキング剤、酸味剤、乳化剤、粘稠剤、懸濁剤、分散または湿潤剤、酸化防止剤等から選択される添加剤を含めた慣用の添加剤を本発明の組成物に含めてもよい。
【００３７】
薬剤または食事サプリメントでは、ピル、非被覆または被覆錠剤、ハードまたはソフトカプセル、糖衣剤、口内錠、経口用溶液、懸濁液及び分散液、シロップ、または滅菌非経口製剤の形態でタンパク質は医薬的に許容され得る担体、賦形剤または希釈剤と混合され得る。好適な賦形剤には、炭酸カルシウム、炭酸ナトリウム、ラクトース、リン酸カルシウム、リン酸ナトリウムのような不活性希釈剤；コーンスターチまたはアルギン酸のような顆粒化剤及び崩壊剤；スターチ、ゼラチンまたはアカシアのような結合剤；ステアリン酸マグネシウム、ステアリン酸またはタルクのような滑沢剤が含まれる。大量の遊離アミノ酸を経口剤型に存在させるときに苦い味を隠すためにカプセル化が推奨され得る。薬剤または食事サプリメントの全重量に基づいて最高７５重量％、好ましくは３０〜７５重量％のタンパク質を含むように薬剤または食事サプリメントを製造することが有利であり得る。
【００３８】
臨床監視下で無月経を治療するためには、栄養アプローチをエストロゲン補充療法のような一般的な薬物療法または大麻のような食欲刺激剤と組み合わせることが可能である。例えば、本発明の組成物はエストロゲンまたはそのアナログと一緒に別個、逐次または同時投与のためのキットの形態で提供され得る。慣用されている医薬成分を一般的な剤型でタンパク質と共に処方され得ることが有利であり得る。
【００３９】
最適には、蛋白様食事サプリメントは正常な月経が再開されるまで定期的に１日に少なくとも１回消費する。タンパク質サプリメントを飲食物の形態で与えるとき、好適な一人分の大きさは２０〜５００ｇ、好ましくは５０〜２５０ｇであり得る。食事または医薬品形態で提供するときには、タンパク質含有組成物を２４時間にわたり１回または数回投与し得る。これらの製剤は安全に消費されるので、摂食障害の症状を発現していたり過剰運動の女性は必要なだけ長期間サプリメントを、好ましくは健康な摂食パターンが再開されるまで摂取し続けることができる。
【実施例１】
【００４０】
タンパク質サプリメントはタンパク質欠乏ラットにおいて月経周期を回復できる。
【００４１】
性ホルモン状態に対するタンパク質摂取の役割を調べるために、６ヶ月令成熟雌Ｓｐｒａｇｕｅ−Ｄａｗｌｅｙラットに１５、７．５、５．０または２．５％のカゼインを含有するラット餌（糖、コーン油、カゼイン塩、コーンスターチ、繊維、ビタミン、ミネラル等）を主成分とする等カロリー食餌を１５週間与えた。タンパク質量の変化を補うためにコーンスターチ含量を調節することにより食餌を等カロリーとした。
【００４２】
ラットではエストロゲンはたった数時間／周期（６日）でピークに達するので、ホルモン状態を直接評価することは技術的に困難である。従って、月経周期の存在及び期間は膣スミア検査により間接的に評価した。
【００４３】
血漿インスリン様成長因子１（ＩＧＦ−１）は、酸−エタノールで抽出し、Ｎｉｃｈｏｌｓ Ｉｎｓｔｉｔｕｔｅのキットを用いて寒冷沈降後ラジオイムノアッセイにより測定した。低ＩＧＦ−１レベルは低食餌タンパク質摂取量、よって低い骨量と相関していると考えられる。
【００４４】
複エネルギーＸ線吸光光度法（ＤＸＡ）測定は、小動物での測定に適合させたＨｏｌｏｇｉｃ ＱＤＲ−１０００器具を用い、超高解像モード（ライン間隔０．２５４ｍｍ及び解像０．１２７ｍｍ）及び０．９ｍｍ直径コリメータを用いて実施した。測定中、動物にケタミン塩酸塩（１００ｍｇ／ｋｇ体重）を用いて麻酔をかけた。
【００４５】
１２週間後、１５、７．５または５．０％のカゼイン含有食餌を与えられたラットはそれぞれ５．６±０．２、５．８±０．３、６．１±０．３日（平均＋ＳＥＭ）の規則的周期を有していたが、２．５％のカゼイン含有食餌を与えられたラットでは周期が全く存在していなかった。
【００４６】
研究から１５週間目、２．５％のカゼイン含有食餌を与えられたラットも近位及び中央骨幹脛骨をＤＸＡにより測定して骨ミネラル密度（ＢＭＤ）の有意な低下を示した。小柱スペースの広がりと共に小柱の容積及び数は有意に減少した。血漿ＩＧＦ−１は研究から３週間まで著しく低下した。
【００４７】
追跡実験で、食物タンパク質追加の効果を上記した種類の低タンパク質食餌（２．５％カゼイン）を予め８週間与えたラット群で調査した。全部で７．５％または１５％のカゼインを含む等カロリー食餌を１６週間投与すると、表１に示すように２．５％カゼイン食餌を予め与えたラットのそれぞれ約６０％及び８０％で周期が回復した。
【００４８】
【表１】
【実施例２】
【００４９】
必須アミノ酸を含む食餌を補充するとタンパク質欠乏ラットの月経周期を回復させることができる。
【００５０】
同一の測定プロトコルを用いて実施例１と同様の実験で、成熟雌ラットに以下のプロトコルに従ってタンパク質組成の異なるラット用等カロリー食餌を与えた：
第１群（ポジティブコントロール）：カゼイン酸カルシウム形態のカゼイン１５％（２０週間）、
第２群（ネガティブコントロール）：カゼイン２．５％（２０週間）、
第３群：カゼイン２．５％（１２週間）後、カゼイン２．５％＋ＥＡＡブレンド２．５％（８週間）、
第４群：カゼイン２．５％（１２週間）後、カゼイン２．５％＋ＥＡＡブレンド５％（８週間）。
【００５１】
ＥＡＡブレンドの組成は次の通りである：
アミノ酸 総ＥＡＡブレンドの重量％
ロイシン ２４．０
リジン １５．０
イソロイシン １１．３
フェニルアラニン １０．９
バリン ９．１
ＤＬ−メチオニン ７．４
Ｌ−アルギニン ６．８
トレオニン ６．６
ヒスチジン ６．５
トリプトファン ２．４。
【００５２】
膣スミアによる月経周期の検査を１２週目及び２０週目に実施した。結果を表１に示す。２３週目にラットを殺した後、卵巣を切開し、秤量した。
【００５３】
【表２】
【００５４】
ラットの重量を０週目、１２週目及び２１週目に測定した。２３週目にラットを殺し、筋肉重量は切開し、脛骨の周りのすべての筋肉を秤量することにより調べた。
【００５５】
【表３】
【００５６】
０週目、１２週目及び２１週目に脊椎、近位脛骨及び中央骨幹脛骨の骨ミネラル密度（ＢＭＤ）をＤＸＡにより測定した。表３に示すように、低カゼイン食餌に応答して３カ所すべてでＢＭＤの低下が見られ、これはＥＡＡにより部分的に逆転可能であるようであった。
【００５７】
【表４】
【００５８】
無月経を患っている栄養不良女性が消費するのに適したＥＡＡブレンドを含む粉末栄養剤
タンパク質：脂肪：炭水化物の割合（ｅｎ％）は２９：１２：５９である。
【００６０】
この組成物を１日少なくとも１回摂取するのに適した一人分の大きさは５０〜７５ｇである。
【００６１】
＊ ＥＡＡミックスは以下の組成（乾燥重量％）
【実施例４】
【００６２】
本発明で使用するのに適したスポーツバー
４０ｇの棒状（１００ｇあたり）：
エネルギー ４１４ｋｃａｌ
タンパク質 ２５．５ｇ
炭水化物 ４８．２ｇ
脂肪 １３．２ｇ
＋ビタミンＥ、Ｃ、Ｂ１、Ｂ２、ナイアシン、Ｂ６、葉酸、Ｂ１２、ビオチン及びパントテン酸の推奨１日用量の５０％。
【実施例５】
【００６３】
本発明で使用するのに適した粉末スポーツドリンク
超高タンパク質処方物（３７３ｋｃａｌ／１００ｇ）
タンパク質（カゼイン塩） ９０ｅｎ％、
脂肪 ５ｅｎ％、
炭水化物 ４．７ｅｎ％、並びに
鉄、亜鉛、及びビタミンＥ、Ｃ、Ｂ１、Ｂ２、ナイアシン、Ｂ６、葉酸、Ｂ１２、ビオチン及びパントテン酸。
【００６４】
高タンパク質処方物（３７２ｋｃａｌ／１００ｇ）
タンパク質 ３３ｅｎ％
脂肪 ２ｅｎ％
炭水化物 ６３．４ｅｎ％
＋鉄、亜鉛、及びビタミンＥ、Ｃ、Ｂ１、Ｂ２、ナイアシン、Ｂ６、葉酸、Ｂ１２、ビオチン及びパントテン酸。【Technical field】
[0001]
The present invention relates to a method for the treatment and prevention of amenorrhea and related medical diseases, in particular a dietary means for reversing said symptoms.
[Background]
[0002]
Recently, anxiety has arisen when diagnosing eating disorders such as anorexia nervosa and bulimia, especially among young women. Diets, often combined with intense exercise, can lead to a very shortage of energy intake. People who sometimes do not consume enough calories to meet energy requirements are athletes who are undergoing intense physical training. In severe malnutrition, the body has adapted by truncating non-essential metabolic processes for survival.
[0003]
Among girls and women, one of the most prominent symptoms of low weight due to severe loss or no weight gain is amenorrhea (ie, no menstrual cycle because ovulation has stopped). The reduced energy intake seen in severe dietary restrictions is thought to be the main cause of amenorrhea in these situations.
[0004]
Amenorrhea for a long time has very serious consequences for health. For example, there is a strong correlation between amenorrhea and fertility. In addition, the low level of circulating estrogen in the blood results in decreased bone mass gain during growth and causes bone loss in adulthood. A low body mass index (BMI) is considered a risk factor for osteoporosis. In women with anorexia nervosa, the serum level of osteocalcin, a bone formation marker, is significantly reduced compared to the level of healthy people who fit age. It is common knowledge that amenorrheic women are prone to osteoporosis and fractures, especially in later years.
[0005]
In order to avoid personal adverse stress caused by infertility and brittle bones and limit the burden on medical personnel involved in the treatment of the disease, treatment that can quickly return the menstrual cycle of amenorrheic women is urgently needed It has been demanded.
[0006]
Ideally, a malnourished amenorrheic woman will spontaneously resume a balanced diet and a sufficient calorie diet. However, this is usually unrealistic because anorexia nervosa and other underfeeding / excessive movement disorders are chronic conditions that can afflict a person for a lifetime. Patients often do not follow general medical advice to increase their calorie content. Similarly, athletes are often interested in keeping the body in peak physical condition and minimizing body fat mass by controlling calorie consumption.
[0007]
Current clinical therapies usually employ estrogen treatment to stop hunger or restore an irregular menstrual cycle. However, this effect is highly suspicious and accompanied by side effects, and it has been noted that estrogen may promote cancer development. Calcium and vitamin D supplements are also often prescribed for bone support in amenorrhea malnourished women. However, the treatment cannot completely eliminate the negative effects of sex hormone deficiency and low protein intake.
[0008]
Applicants can rapidly resume normal hormonal cycles and menstruation with diet and increase bone mineral density (BMD) and weight in women experiencing amenorrhea due to weight loss An unprecedented experimental result was obtained. To obtain the above results, it is important to increase dietary protein intake. Unexpectedly, essential amino acid blends are just as effective as complete dietary protein. Unexpectedly, the desired effect is obtained without increasing the total energy consumption, in some cases. Thus, this method of treatment is ideally suited for amenorrheal women who do not want to increase their total caloric intake, especially those who do not like fat or carbohydrate consumption.
[0009]
Protein supplements or diets to treat amenorrhea due to weight loss can be self-administered for long periods without the risk of side effects, to prevent long-term damage to the body due to poor sex hormone balance It is very effective.
DISCLOSURE OF THE INVENTION
[0010]
According to a first aspect of the invention, two or more free or salt forms in the manufacture of a medicament or nutrient for returning estrogen levels in a premenopausal woman suffering from malnutrition to a physiologically normal level Provides use of essential amino acids.
[0011]
According to another aspect of the invention, two or more free forms in the manufacture of a medicament or nutrient for the prevention or treatment of amenorrhea, undermenstrual or vagus menstruation, in particular these diseases caused by malnutrition, or The use of essential amino acids in salt form is provided.
[0012]
According to a further aspect of the present invention, two in the manufacture of a medicament or nutrient for preventing or treating osteopenia or osteoporosis in premenopausal women suffering from amenorrhea, undermenorrhea or vagus menstruation Provided is the use of the essential amino acids in free or salt form.
[0013]
According to a further aspect of the present invention, a medicament or nutrition for preventing or reversing weight loss and / or muscle mass loss in a premenopausal woman suffering from amenorrhea, undermenstrual or vagus menstruation due to malnutrition The use of two or more free or salt forms of essential amino acids in the manufacture of the agent is provided.
[0014]
According to a further aspect of the invention, there is provided at least 20 en% protein for the prevention or treatment of amenorrhea, undermenstrual or vagus menstruation in premenopausal women suffering from malnutrition, carbonated or carbonated soft Drink, juice, sports drink, milk drink, milk shake, yogurt drink, smoothie, soy-based drink, soup, stick cereal, stick dairy, snack food, breakfast cereal, candy, tab, cookie, cracker, chocolate, chewing gum or Providing the use of proteins in medicines or nutrients that are in the form of desserts.
[0015]
According to a further aspect of the present invention, at least 20 en% for preventing or treating osteopenia or osteoporosis due to malnutrition in a premenstrual woman suffering from amenorrhea, undermenorrhea or vagus menstruation The use of the protein in the manufacture of a fully formulated diet or enteral nutritional supplement containing the protein of
[0016]
According to a further aspect of the invention, a complete prescription diet or enteral nutrition comprising at least 20 en% protein for preventing or treating amenorrhea, undermenstrual or vagus menstruation in premenopausal women suffering from malnutrition Providing the use of proteins in the manufacture of replenishers.
[0017]
According to a further aspect of the invention, osteopenia, osteoporosis, amenorrhea comprising a blend of amino acids consisting of leucine, lysine, isoleucine, phenylalanine, valine, arginine, threonine, histidine and tryptophan in free or salt form. A pharmaceutical or nutritional composition for preventing or treating undermenstrual or vagus menstruation is provided.
[0018]
(Detailed description of the invention)
The methods of the present invention can be applied to normally undernourished or malnourished women. As used herein, the term “female” refers to premenopausal women as well as girls approaching puberty (before puberty) or after puberty. Many women impose diets in their lifetime and potentially have the risk of lowering blood estrogen levels or affecting bone calcifications, so malnutrition and nutrition The number of women in shortage is large. Many women in underdeveloped countries are also chronically undernourished or starved due to food shortages, and the method of the present invention is a simple but practical way to restore women's health.
[0019]
Young (15-35 year old) women who are undernourished are most likely to benefit from the treatment method of the present invention. This is because the bone mass reaches a peak around this time, and if the bone density does not increase around this vulnerable year, it is likely that later women will suffer from osteoporosis. Patients with bone density exceeding 2 standard deviations below normal for age and sex should receive immediate treatment as described herein to stop and preferably reverse bone loss . Women between the ages of 15 and 35 want most to get pregnant and therefore want to minimize the negative effects on fertility due to malnutrition.
[0020]
For the reasons mentioned above, amenorrhea or undermenstrual patients suffering from eating disorders such as anorexia nervosa and bulimia nervosa must be urgently careful to avoid irreversible damage to the reproductive system and skeleton. , The main subject of the treatment methods described herein. Other subjects intended for the treatment include very active women, especially dancers and endurance athletes. Women who are underweight but restrict or are trying to limit energy intake for weight loss purposes, and vegetarians, strict vegetarians, or women who have an unbalanced diet to maintain a normal menstrual cycle Is also a suitable subject of the treatment method of the present invention.
[0021]
Malnutrition is a chronic undernourishment or starvation condition that can occur because caloric intake is repeatedly lacking more than is necessary to balance the body's catabolism or because the diet composition is unbalanced. possible. Analysis by dietary nutritionists, dietitians or other professionals will indicate whether an individual is malnourished or at risk of becoming malnourished. In the present invention, malnutrition is considered to be known at low body weight and / or low body fat mass and / or low serum leptin concentration. Underweight is defined as a BMI of less than 20, especially less than 18. A body fat mass of about 15-17% or less is considered low. Since there is a correlation between body fat mass and leptin level, the treatment method of the present invention is started to prevent or ameliorate menstrual abnormalities when the serum concentration of this hormone is less than 5 ng / ml, especially less than 1.85 ng / ml Should.
[0022]
In the present invention, amenorrhea is defined as a state in which there is no menstruation in a pre-menopausal woman who is not pregnant, especially 6 months or more. There is no menarche in primary amenorrhea, ie menstruation has never happened. In secondary (hypothalamic) amenorrhea, menstruation stops after at least one cycle. Undermenstrual periods are defined as cases where menstrual bleeding is no more than 3 times per year over 2 years. The treatment methods of the present invention are particularly applicable to low body weight / body fat mass, or amenorrhea with a rapid weight loss (primary or secondary), undermenstrual periods, or vagal or irregular menstruation obtain. One purpose of the treatment method of the present invention is to return the menstrual cycle to a regular cycle at a frequency that is considered normal for women. To define the present invention, the normal physiological level of estrogen is ≧ 30 pg / ml serum estradiol, and ovulation will not resume unless it is 30 pg / ml or higher. Serum estradiol is preferably restored to a value in the range of 100-700 pg / ml, most preferably 200-400 pg / ml. Even if menstruation recovers only partially or irregularly, it may show a partial recovery of circulating estrogen levels with improved bone mineral density (BMD).
[0023]
One of the greatest effects of the improved amenorrhea treatment method of the present invention is that, contrary to conventional methods, there is no need to increase the total energy content of the diet to reverse symptoms. In fact, simply increasing the ratio of protein to the other major components of the diet (fats and carbohydrates) while maintaining an isocaloric amount is a surprisingly effective way to restore a normal menstrual cycle. As a result, women who do not want to increase caloric intake, such as women suffering from anorexia nervosa and other eating disorders, are more likely to accept this new and improved treatment than conventional methods involving forced nutrition. For the purposes of the present invention, changes of ± 10% or less, especially ± 5% or less of the total calories of the meal are considered to be substantially unchanged. That is, the meal is isocaloric.
[0024]
The following examples show that low BMI seen in response to nutritional deficiencies such as protein deficiency can be significantly improved by increasing the proportion of protein (casein or essential amino acid (EAA) blend) in the diet. Indicates. This result is medically amazing. This is because, for the first time, it has been demonstrated that skeletal weakness associated with malnutrition can be recovered in premenopausal women by changing the composition of the diet without the need for treatment with estrogen or other drugs. Perhaps the main effect of adding protein is to restore estrogen secretion and the menstrual cycle and ultimately affect bone structure. Thus, the method of the present invention is effective for premenopausal women who suffer from or are at risk of suffering from osteopenia and osteoporosis due to malnutrition.
[0025]
The agent or nutrient of the present invention may be composed exclusively of protein, or may contain other nutritional components in addition to protein. As used herein, “protein” or “proteinaceous material” refers to digestible proteins, peptides, single amino acids, amino acid mixtures and combinations thereof. Preferred proteins are milk protein, casein, whey and hydrolysates or peptides thereof, egg proteins, plant proteins (eg, soy protein, pea protein, rice protein or wheat protein), free amino acids and mixtures thereof. When referring to an amino acid, the term is understood to encompass the L form or other isomers of the free amino acid in hydrated or anhydrous form, as well as salts of said amino acid.
[0026]
In particular, it is preferable that one or more, preferably at least two essential amino acids are added to the protein component of the composition of the present invention. Essential amino acids (EAA) are histidine, isoleucine, leucine, lysine, methionine, phenylalanine, threonine, tryptophan and valine. In one embodiment of the invention, the protein component of the composition of the invention comprises at least 30% by weight (preferably at least 45% by weight) of branched chain amino acids (valine, isoleucine, leucine). “EAA blend” or “EAA composition” should be understood to refer to a composition comprising at least one EAA. The particular amino acid blend selected may vary depending on the patient being treated. For example, vegetarians or strict vegetarians can benefit greatly from products containing amino acids that are not present in plant material. If the patient to be treated with the method of the present invention is anorexic or does not want to eat, it is postulated that serotonin levels and anorexia are related so that the free amino acid form of the composition It may be recommended not to incorporate tryptophan. Optionally, a mixture of all essential amino acids except methionine can be used for humans.
[0027]
In a preferred embodiment of the present invention, the protein incorporated in the special diet of the present invention comprises a blend of one or more amino acids selected from leucine, lysine, isoleucine, phenylalanine, valine, arginine, threonine, histidine and tryptophan. Optionally, additional proteins may be added. For example, amino acids are based on weight with the following relative ratio:
Leucine 1.0-1.5
Lysine 0.75-1.0
Isoleucine 0.4-0.75
Phenylalanine 0.35-0.6
Valine 0.25-0.6
Arginine 0.25-0.6
Threonine 0.25-0.5
Histidine 0.25-0.5
Tryptophan 0-0.25
Can exist in
[0028]
Particularly preferred formulations are 24 to 28% leucine, 14 to 18% lysine, 10 to 14% isoleucine, 10 to 14% phenylalanine, 8 to 12% valine, 6% by weight based on the total weight of amino acids. It has an amino acid composition of -8% arginine, 6-8% threonine, 6-8% histidine and 2-3% tryptophan.
[0029]
Optionally, the protein component of the composition of the present invention is composed exclusively or essentially of a blend of free amino acids as described herein. More generally, the protein component comprises total protein and free amino acids, preferably in a weight ratio of 1: 5 to 5: 1. Formulations containing whey protein with a blend of essential amino acids may be used. In a preferred embodiment of the invention, the protein component comprises whey protein and amino acid blend in a weight ratio of about 2: 1 to 4: 1, preferably about 3: 1. The total protein content of the nutrients or medicaments of the present invention is preferably at least 20 en% (energy%), or at least 25 en%, such as 25-100 en%, preferably 30-90 en%, based on the total calories of the nutrient or medicament Most preferably, it is 40-80 en%.
[0030]
Optionally, the protein is provided in the form of a nutritionally balanced complete diet suitable for oral or tube feeding. A complete or complete diet that meets all nutritional requirements includes fat and carbohydrates in addition to protein, and (soluble and / or insoluble) fiber, minerals and vitamins. For a prescription or other form of balanced nutrition, the protein: fat: carbohydrate relative ratio (en%) is optionally 25-35: 8-30: 40-65. It may be desirable to provide the protein in the form of a low calorie meal or other nutritional food. In this case, the low calorie meal or other nutritional diet is preferably low fat (ie, <10 en%) or substantially fat free (ie, less than 2.5 en%, eg, about 2 en%). Suitably, a serving of low calorie substitute food has a caloric value of less than 1000 kcal, preferably 200-500 kcal.
[0031]
Alternatively, the protein is provided as a dietary supplement that is included in the meal so that the desired amount of protein or caloric content from the protein is achieved. The total desired caloric content of protein in the meal is at least 25 en%, more preferably at least 30 en%.
[0032]
According to the dietary regimen of the present invention, it is contemplated that women will consume a total of at least 10 g / day, preferably 15-200 g / day, most preferably 20-100 g / day of protein.
[0033]
The agents or nutrients of the invention can be administered under the supervision of a medical professional or can be self-administered.
[0034]
For convenience, protein / amino acid containing formulations are as a complete meal, as a dissolving powder (eg hot chocolate or health drink), as a solution, as a soft drink including juice, milk shake, yogurt drink, smoothie or soy based drink In some cases, it can be provided as a low-calorie ready-to-use drink in a bar-shaped oral nutritional form, or baked food, cereal bar, bar-shaped dairy product, snack food, soup, breakfast cereal, mousse, candy, tab, It can be dispersed in any type of food such as cookies, biscuits, crackers (eg rice crackers), chocolate and dairy products. For physically active women, especially overexercised women such as sportswomen, dancers and anorexia nervosa, sports drinks are a very convenient way to give protein supplements. Preferably, the sports drink is isotonic and comprises an electrolyte and a source of sugar or artificial sweetener. Optionally, the formulation can be administered in the form of a feeding tube supplement or intravenously.
[0035]
In a preferred embodiment of the invention, the protein component of the invention is administered in a pharmaceutical or nutritional composition that also contains one or more of calcium, magnesium, iron, zinc, phosphorus, vitamin D and vitamin K. A suitable daily dose is 0.1 mg to 3.6 g, preferably 320 to 530 mg, particularly preferably about 500 mg of calcium. Usually, the daily doses of vitamins and minerals in the nutrients or medicaments of the present invention are 25-100% by weight, most preferably 35-50% by weight of the dose recommended by health professionals. Dietary fiber can also be a component of the composition of the present invention. For example, the fiber component may be present from 0 to 15%, preferably from 2 to 10%, most preferably from 3 to 5% by weight based on the total weight of the composition. Additional ingredients of supplements include bioactive compounds or extracts known to be healthy, especially bioactive compounds or extracts for bone construction, regulation of hormone imbalance and / or improvement of physical function. obtain.
[0036]
Selected from preservatives, chelating agents, saturants, natural or artificial sweeteners, flavors, colorants, taste masking agents, acidulants, emulsifiers, thickeners, suspending agents, dispersing or wetting agents, antioxidants, etc. Conventional additives, including additives, may be included in the compositions of the present invention.
[0037]
For drug or dietary supplements, proteins are pharmaceutically available in the form of pills, uncoated or coated tablets, hard or soft capsules, dragees, oral tablets, oral solutions, suspensions and dispersions, syrups, or sterile parenteral formulations. It can be mixed with an acceptable carrier, excipient or diluent. Suitable excipients include inert diluents such as calcium carbonate, sodium carbonate, lactose, calcium phosphate, sodium phosphate; granulating and disintegrating agents such as corn starch or alginic acid; starch, gelatin or acacia Binders; include lubricants such as magnesium stearate, stearic acid or talc. Encapsulation may be recommended to mask the bitter taste when large amounts of free amino acids are present in the oral dosage form. It may be advantageous to produce a drug or dietary supplement to contain up to 75%, preferably 30-75% protein by weight based on the total weight of the drug or dietary supplement.
[0038]
In order to treat amenorrhea under clinical supervision, it is possible to combine nutritional approaches with common medications such as estrogen replacement therapy or appetite stimulants such as cannabis. For example, the compositions of the present invention may be provided in the form of a kit for separate, sequential or simultaneous administration with estrogen or analog thereof. It may be advantageous to be able to formulate conventional pharmaceutical ingredients with proteins in a common dosage form.
[0039]
Optimally, proteinaceous dietary supplements are regularly consumed at least once a day until normal menstruation is resumed. When protein supplements are given in the form of food and drink, a suitable serving size may be 20-500 g, preferably 50-250 g. When provided in a meal or pharmaceutical form, the protein-containing composition may be administered once or several times over a 24 hour period. Because these products are consumed safely, women who develop symptoms of eating disorders or overexercise should continue to take supplements for as long as necessary, preferably until healthy eating patterns are resumed. Can do.
[Example 1]
[0040]
Protein supplements can restore the menstrual cycle in protein-deficient rats.
[0041]
To investigate the role of protein intake on sex hormone status, 6-month-old female Sprague-Dawley rats were fed rat diets containing 15, 7.5, 5.0 or 2.5% casein (sugar, corn oil, An isocaloric diet mainly composed of casein salt, corn starch, fiber, vitamins, minerals, etc.) was given for 15 weeks. The diet was made isocaloric by adjusting the corn starch content to compensate for changes in protein content.
[0042]
In rats, estrogen peaks in just a few hours / cycle (6 days), so it is technically difficult to assess hormonal status directly. Therefore, the presence and duration of the menstrual cycle was indirectly assessed by vaginal smear testing.
[0043]
Plasma insulin-like growth factor 1 (IGF-1) was extracted with acid-ethanol and measured by radioimmunoassay after cryoprecipitation using a Nichols Institute kit. Low IGF-1 levels are thought to correlate with low dietary protein intake and thus low bone mass.
[0044]
Double energy X-ray absorptiometry (DXA) measurements were made using a Horological QDR-1000 instrument adapted for small animal measurements, with ultra-high resolution mode (line spacing 0.254 mm and resolution 0.127 mm) and 0. This was performed using a 9 mm diameter collimator. During the measurement, the animals were anesthetized with ketamine hydrochloride (100 mg / kg body weight).
[0045]
After 12 weeks, rats fed a diet containing 15, 7.5 or 5.0% casein were 5.6 ± 0.2, 5.8 ± 0.3, 6.1 ± 0.3 days, respectively ( There was a regular cycle of (mean + SEM), but there was no cycle at all in rats fed a diet containing 2.5% casein.
[0046]
At 15 weeks from the study, rats fed a diet containing 2.5% casein also showed a significant decrease in bone mineral density (BMD) as measured by DXA on the proximal and central diaphysis. As the trabecular space expanded, the trabecular volume and number decreased significantly. Plasma IGF-1 was significantly reduced up to 3 weeks from the study.
[0047]
In a follow-up experiment, the effect of adding food protein was investigated in a group of rats that had previously been given a low protein diet of the type described above (2.5% casein) for 8 weeks. Administration of an isocaloric diet containing a total of 7.5% or 15% casein for 16 weeks results in a cycle in approximately 60% and 80% of rats pre-fed with 2.5% casein diet as shown in Table 1, respectively. Recovered.
[0048]
[Table 1]
[Example 2]
[0049]
Supplementation with a diet containing essential amino acids can restore the menstrual cycle of protein-deficient rats.
[0050]
In an experiment similar to Example 1 using the same measurement protocol, adult female rats were fed an isocaloric diet for rats with different protein compositions according to the following protocol:
Group 1 (positive control): Casein 15% calcium caseinate (20 weeks),
Group 2 (negative control): Casein 2.5% (20 weeks),
Group 3: Casein 2.5% (12 weeks) followed by casein 2.5% + EAA blend 2.5% (8 weeks)
Group 4: Casein 2.5% (12 weeks) followed by Casein 2.5% + EAA blend 5% (8 weeks).
[0051]
The composition of the EAA blend is as follows:
amino acid % By weight of total EAA blend
Leucine 24.0
Lysine 15.0
Isoleucine 11.3
Phenylalanine 10.9
Valine 9.1
DL-methionine 7.4
L-Arginine 6.8
Threonine 6.6
Histidine 6.5
Tryptophan 2.4.
[0052]
Examination of the menstrual cycle with vaginal smear was performed at 12 and 20 weeks. The results are shown in Table 1. After killing the rats at week 23, the ovaries were dissected and weighed.
[0053]
[Table 2]
[0054]
Rat weights were measured at 0, 12, and 21 weeks. At week 23, the rats were killed and the muscle weight was incised and examined by weighing all muscles around the tibia.
[0055]
[Table 3]
[0056]
Bone mineral density (BMD) of the spine, proximal tibia, and midshaft tibia was measured by DXA at 0, 12 and 21 weeks. As shown in Table 3, there was a decrease in BMD in all three places in response to a low casein diet, which appeared to be partially reversible by EAA.
[0057]
[Table 4]
[0058]
Powdered nutritional supplement containing an EAA blend suitable for consumption by malnourished women suffering from amenorrhea
The protein: fat: carbohydrate ratio (en%) is 29:12:59.
[0060]
A suitable serving size for taking this composition at least once a day is 50-75 g.
[0061]
* The EAA mix has the following composition (dry weight%)
[Example 4]
[0062]
Sports bar suitable for use in the present invention
40g rod shape (per 100g):
Energy 414 kcal
25.5g protein
Carbohydrate 48.2g
13.2 g of fat
+ 50% of the recommended daily dose of vitamins E, C, B1, B2, niacin, B6, folic acid, B12, biotin and pantothenic acid.
[Example 5]
[0063]
Powdered sports drink suitable for use in the present invention
Ultra-high protein formulation(373kcal / 100g)
Protein (casein salt) 90en%,
5en% fat,
4.7 en% carbohydrates, and
Iron, zinc, and vitamins E, C, B1, B2, niacin, B6, folic acid, B12, biotin and pantothenic acid.
[0064]
High protein formulation(372kcal / 100g)
Protein 33en%
Fat 2en%
Carbohydrate 63.4en%
+ Iron, zinc, and vitamins E, C, B1, B2, niacin, B6, folic acid, B12, biotin and pantothenic acid.
Claims (27)
ロイシン １．０−１．５
リジン ０．７５−１．０
イソロイシン ０．４−０．７５
フェニルアラニン ０．３５−０．６
バリン ０．２５−０．６
アルギニン ０．２５−０．６
トレオニン ０．２５−０．５
ヒスチジン ０．２５−０．５
トリプトファン ０−０．２５
で含む請求の範囲第１項〜第５項のいずれかに記載の使用。The following relative ratios, based on weight, of a blend of amino acids in which the drug or nutrient is in free or salt form:
Leucine 1.0-1.5
Lysine 0.75-1.0
Isoleucine 0.4-0.75
Phenylalanine 0.35-0.6
Valine 0.25-0.6
Arginine 0.25-0.6
Threonine 0.25-0.5
Histidine 0.25-0.5
Tryptophan 0-0.25
The use according to any one of claims 1 to 5, comprising:
ロイシン １．０−１．５
リジン ０．７５−１．０
イソロイシン ０．４−０．７５
フェニルアラニン ０．３５−０．６
バリン ０．２５−０．６
アルギニン ０．２５−０．６
トレオニン ０．２５−０．５
ヒスチジン ０．２５−０．５
トリプトファン ０−０．２５
で含む請求の範囲第１３項に記載の医薬または栄養組成物。The composition has the following relative ratios based on weight of amino acids:
Leucine 1.0-1.5
Lysine 0.75-1.0
Isoleucine 0.4-0.75
Phenylalanine 0.35-0.6
Valine 0.25-0.6
Arginine 0.25-0.6
Threonine 0.25-0.5
Histidine 0.25-0.5
Tryptophan 0-0.25
14. A pharmaceutical or nutritional composition according to claim 13 comprising
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| GBGB0110288.8A GB0110288D0 (en) | 2001-04-26 | 2001-04-26 | Composition and treatment method |
| PCT/EP2002/004615 WO2002087562A1 (en) | 2001-04-26 | 2002-04-25 | Use of protein and essential amino acids to treat amenorrhea and related disorders |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| JP2005505500A true JP2005505500A (en) | 2005-02-24 |
| JP2005505500A5 JP2005505500A5 (en) | 2005-12-22 |
Family
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| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP2002584908A Pending JP2005505500A (en) | 2001-04-26 | 2002-04-25 | Use of proteins and essential amino acids to treat amenorrhea and related diseases |
Country Status (8)
| Country | Link |
|---|---|
| US (1) | US20040171690A1 (en) |
| EP (1) | EP1392275A1 (en) |
| JP (1) | JP2005505500A (en) |
| BR (1) | BR0209245A (en) |
| CA (1) | CA2445343A1 (en) |
| GB (1) | GB0110288D0 (en) |
| WO (1) | WO2002087562A1 (en) |
| ZA (1) | ZA200308311B (en) |
Cited By (6)
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| WO2011103329A3 (en) * | 2010-02-17 | 2011-10-13 | Western Holdings, Llc | Weight loss method and system for performing and monitoring the same |
| JP2012062309A (en) * | 2010-08-19 | 2012-03-29 | Nisshin Pharma Inc | Composition for muscular increase |
| JP2012239383A (en) * | 2011-05-13 | 2012-12-10 | Uha Mikakuto Co Ltd | Chocolate |
| WO2014132985A1 (en) * | 2013-02-26 | 2014-09-04 | 味の素株式会社 | Nutrition composition |
| JP2016190842A (en) * | 2015-03-30 | 2016-11-10 | 国立大学法人 岡山大学 | Bone formation promoter |
| JP2019140952A (en) * | 2018-02-19 | 2019-08-29 | 株式会社コンプ | Oral ingestion nutrition adjustment food |
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| US20040087490A1 (en) | 2002-09-20 | 2004-05-06 | Troup John P. | Nutritional compositions |
| US7288570B2 (en) * | 2002-12-20 | 2007-10-30 | Nutricia N.V. | Stimulation of in vivo production of proteins |
| GB0320990D0 (en) * | 2003-09-08 | 2003-10-08 | Unilever Plc | Food composition |
| JP4815752B2 (en) * | 2004-04-01 | 2011-11-16 | 味の素株式会社 | Amino acid-containing foods and drinks |
| JP4534579B2 (en) * | 2004-04-28 | 2010-09-01 | 味の素株式会社 | Lysine-containing anti-obesity or anti-hyperlipidemic food, feed or supplement |
| DE502006008291D1 (en) * | 2005-08-23 | 2010-12-23 | Herberger Armand | PROTEIN COMPOSITION FOR TREATING A PHYSIOLOGICALLY CONDITIONAL, CLINICALLY INVALID PROTEIN SUPPLY |
| WO2007022968A1 (en) * | 2005-08-23 | 2007-03-01 | Hans Leweling | Protein composition for treating protein deficiency conditions |
| US7982066B2 (en) * | 2005-12-09 | 2011-07-19 | Novalife, Inc. | High protein supplement |
| US9132161B2 (en) * | 2007-09-07 | 2015-09-15 | Bionovo, Inc. | Estrogenic extracts of Rheum palmatum L of the polygonaceae family and uses thereof |
| NL2007080C2 (en) * | 2011-07-11 | 2013-01-14 | Fredericus Franciscus Carolus Bergmans | Supplemented food product and nutritional supplement for use in the treatment of malnutrition. |
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| US4025650A (en) * | 1975-11-24 | 1977-05-24 | Control Drug, Inc. | Method and composition for preventing nutritional deficiency |
| US4352814A (en) * | 1979-04-18 | 1982-10-05 | The Johns Hopkins University | Treatment of hepatic and renal disorders with mixed salts of essential or semi-essential amino acids and nitrogen-free analogs |
| US5230902A (en) * | 1988-04-29 | 1993-07-27 | Immunotec Research Corporation | Undenatured whey protein concentrate to improve active systemic humoral immune response |
| JP2537406B2 (en) * | 1989-05-19 | 1996-09-25 | 株式会社大塚製薬工場 | Amino acid preparation for cancer |
| US6221836B1 (en) * | 1996-07-26 | 2001-04-24 | Paxton King Beale | Composition of pyruvate and anabolic protein and method for increasing fat loss in a mammal |
| US5976568A (en) * | 1997-02-21 | 1999-11-02 | Medical Doctors' Research Institute, Inc. | Modular system of dietary supplement compositions for optimizing health benefits and methods |
-
2001
- 2001-04-26 GB GBGB0110288.8A patent/GB0110288D0/en not_active Ceased
-
2002
- 2002-04-25 US US10/475,950 patent/US20040171690A1/en not_active Abandoned
- 2002-04-25 WO PCT/EP2002/004615 patent/WO2002087562A1/en active Application Filing
- 2002-04-25 EP EP02766638A patent/EP1392275A1/en not_active Withdrawn
- 2002-04-25 JP JP2002584908A patent/JP2005505500A/en active Pending
- 2002-04-25 BR BR0209245-0A patent/BR0209245A/en not_active IP Right Cessation
- 2002-04-25 CA CA002445343A patent/CA2445343A1/en not_active Abandoned
-
2003
- 2003-10-24 ZA ZA200308311A patent/ZA200308311B/en unknown
Cited By (9)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2011103329A3 (en) * | 2010-02-17 | 2011-10-13 | Western Holdings, Llc | Weight loss method and system for performing and monitoring the same |
| JP2012062309A (en) * | 2010-08-19 | 2012-03-29 | Nisshin Pharma Inc | Composition for muscular increase |
| JP2012239383A (en) * | 2011-05-13 | 2012-12-10 | Uha Mikakuto Co Ltd | Chocolate |
| WO2014132985A1 (en) * | 2013-02-26 | 2014-09-04 | 味の素株式会社 | Nutrition composition |
| JPWO2014132985A1 (en) * | 2013-02-26 | 2017-02-02 | 味の素株式会社 | Nutritional composition |
| JP2019108364A (en) * | 2013-02-26 | 2019-07-04 | 味の素株式会社 | Nutritive composition |
| US10765663B2 (en) | 2013-02-26 | 2020-09-08 | Ajinomoto Co., Inc. | Nutrition composition |
| JP2016190842A (en) * | 2015-03-30 | 2016-11-10 | 国立大学法人 岡山大学 | Bone formation promoter |
| JP2019140952A (en) * | 2018-02-19 | 2019-08-29 | 株式会社コンプ | Oral ingestion nutrition adjustment food |
Also Published As
| Publication number | Publication date |
|---|---|
| EP1392275A1 (en) | 2004-03-03 |
| CA2445343A1 (en) | 2002-11-07 |
| GB0110288D0 (en) | 2001-06-20 |
| WO2002087562A1 (en) | 2002-11-07 |
| ZA200308311B (en) | 2004-05-21 |
| BR0209245A (en) | 2004-06-15 |
| US20040171690A1 (en) | 2004-09-02 |
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